Q-TWiST analysis of survival benefits with brigatinib versus crizotinib in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer based on results of the ALTA-1L trial.

OBJECTIVES: The ALTA-1L phase 3 open-label trial demonstrated increased progression-free survival (PFS) with brigatinib versus crizotinib in patients with anaplastic lymphoma kinase-positive (ALK-positive) locally advanced or metastatic non-small cell lung cancer (NSCLC) previously untreated with ALK-targeted therapy. This post-hoc analysis of data from the ALTA-1L trial used the quality-adjusted (QA) time without symptoms of disease or toxicity (Q-TWiST) methodology to compare the QA survival benefit of brigatinib versus crizotinib in this patient population. PATIENTS AND METHODS: The Q-TWiST analysis was performed using final (January 29, 2021) individual patient-level blinded independent review committee (BIRC)- and investigator-assessed survival data for brigatinib (n = 137) and crizotinib (n = 138) in adult patients (N = 275) with ALK-positive locally advanced or metastatic NSCLC previously untreated with ALK-targeted therapy. Q-TWiST was compared between the two treatments. Subgroup analyses were performed in patients stratified by various clinicopathological characteristics, including presence or absence of brain metastases at baseline. RESULTS: Brigatinib was associated with significantly longer time without symptoms of disease or toxicity (P < 0.001) than crizotinib, with significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 28.2 [1.2] versus 25.1 [1.1], P = 0.045; investigator-assessed, 28.5 [1.2] versus 24.8 [1.1], P = 0.018). Relative gains in Q-TWiST with brigatinib compared to crizotinib were clinically meaningful (BIRC-assessed, 10.4%; investigator-assessed, 12.3%). Patients with brain metastases at baseline receiving brigatinib had significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 29.0 [1.9] versus 19.0 [1.9], P = 0.0001) than those receiving crizotinib. CONCLUSION: First-line brigatinib treatment was associated with significant and clinically meaningful gains in Q-TWiST compared to crizotinib in patients with ALK-positive locally advanced or metastatic NSCLC, supporting the results of the ALTA-1L trial and brigatinib as a safe and effective first-line treatment for ALK-positive NSCLC.

[Anatomical classification of and laparoscopic surgery for left-sided colorectal cancer with persistent descending mesocolon].

Objective: To investigate anatomical morphology and classification of persistent descending mesocolon (PDM) in patients with left-sided colorectal cancer, as well as the safety of laparoscopic radical surgery for these patients. Methods: This is a descriptive study of case series. Relevant clinical data of 995 patients with left colon and rectal cancer who had undergone radical surgery in Fujian Medical University Union Hospital from July 2021 to September 2022 were extracted from the colorectal surgery database of our institution and retrospectively analyzed. Twenty-four (2.4%) were identified as PDM and their imaging data and intra-operative videos were reviewed. We determined the distribution and morphology of the descending colon and mesocolon, and evaluated the feasibility and complications of laparoscopic surgery. We classified PDM according to its anatomical characteristics as follows: Type 0: PDM combined with malrotation of the midgut or persistent ascending mesocolon; Type 1: unfixed mesocolon at the junction between transverse and descending colon; Type 2: PDM with descending colon shifted medially (Type 2A) or to the right side (Type 2B) of the abdominal aorta at the level of the origin of the inferior mesentery artery (IMA); and Type 3: the mesocolon of the descending-sigmoid junction unfixed and the descending colon shifted medially and caudally to the origin of IMA. Results: The diagnosis of PDM was determined based on preoperative imaging findings in 9 of the 24 patients (37.5%) with left-sided colorectal cancer, while the remaining diagnoses were made during intraoperative assessment. Among 24 patients, 22 were male and 2 were female. The mean age was (63±9) years. We classified PDM as follows: Type 0 accounted for 4.2% (1/24); Type 1 for 8.3% (2/24); Types 2A and 2B for 37.5% (9/24) and 25.0% (6/24), respectively; and Type 3 accounted for 25.0% (6/24). All patients with PDM had adhesions of the mesocolon that required adhesiolysis. Additionally, 20 (83.3%) of them had adhesions between the mesentery of the ileum and colon. Twelve patients (50.0%) required mobilization of the splenic flexure. The inferior mesenteric artery branches had a common trunk in 14 patients (58.3%). Twenty-four patients underwent D3 surgery without conversion to laparotomy; the origin of the IMA being preserved in 22 (91.7%) of them. Proximal colon ischemia occurred intraoperatively in two patients (8.3%) who had undergone high ligation at the origin of the IMA. One of these patients had a juxta-anal low rectal cancer and underwent intersphincteric abdominoperineal resection because of poor preoperative anal function. Laparoscopic subtotal colectomy was considered necessary for the other patient. The duration of surgery was (260±100) minutes and the median estimated blood loss was 50 (20-200) mL. The median number of No. 253 lymph nodes harvested was 3 (0-20), and one patient (4.2%) had No.253 nodal metastases. The median postoperative hospital stay was 8 (4-23) days, and the incidence of complications 16.7% (4/24). There were no instances of postoperative colon ischemia or necrosis observed. One patient (4.2%) with stage IIA rectal cancer developed Grade B (Clavien-Dindo III) anastomotic leak and underwent elective ileostomy. The other complications were Grade I-II. Conclusions: PDM is frequently associated with mesenteric adhesions. Our proposed classification can assist surgeons in identifying the descending colon and mesocolon during adhesion lysis in laparoscopic surgery. It is crucial to protect the colorectal blood supply at the resection margin to minimize the need for unplanned extended colectomy, the Hartmann procedure, or permanent stomas.

[Surgical treatment for perihilar cholangiocarcinoma:a single-center experience].

Objective: To investigate surgical strategies and the corresponding benefits for patients with perihilar cholangiocarcinoma(pCCA). Methods: A total of 81 patients with pCCA who underwent radical excision in the Department of Biliary and Pancreatic Surgery of Sun Yat-Sen Memorial Hospital between January 2014 and December 2021 were retrospectively collected.The cohort consisted of 50 male and 31 female patients,with an age of (62.5±11.5)years(range:26 to 83 years).Seventy-five cases were diagnosed with jaundice,60 of whom received preoperative biliary drainage,while 20 patients received portal vein embolization.Their serum bilirubin level within one week before the operation(M(IQR)) was 44.3 (41.9) µmol/L(range:8.0 to 344.2 µmol/L).Preoperative imaging examinations were performed to evaluate the Bismuth-Corlette type of pCCA,showing 3,6,21,27,and 24 cases of Bismuth-Corlette type Ⅰ,Ⅱ,Ⅲa,Ⅲb,and Ⅳ,respectively.The primary outcome was overall survival (OS),and the secondary outcomes were relapse-free survival (RFS),90-day postoperative morbidity and 90-day postoperative mortality.OS and RFS were estimated using the Kaplan-Meier method and compared by the Log-rank test.Significant prognostic factors were determined using univariate and multivariable Cox proportional hazard regression analyses. Results: In the cohort of 81 pCCA patients,67 cases(82.7%) underwent major hepatectomy while 3 cases received major hepatectomy combined with pancreaticoduodenectomy.Thirty-four patients underwent hepatectomy combined with vascular resection and reconstruction(18 cases of portal vein resection and reconstruction alone;9 cases of hepatic artery resection and reconstruction alone;7 cases of combination of portal vein and hepatic artery resection and reconstruction).Margin negative(R0 excision) were achieved in 53.1%(43/81) of these patients.The operation duration was (627±136)minutes(range:565 to 940 minutes),and the intraoperative blood loss was 400(455)ml(range:200 to 2 800 ml).The 90-day postoperative mortality was 3.7%(3/81).Grade 3-4 postoperative morbidity was 23.4% (19/81) according to the Clavien-Dindo classification of surgical complications.Up to the last follow-up at September 2022,the follow-up time was 34.0(24.2)months (range:0.4 to 103.6 months).Three patients who died within 90 days after surgery were excluded from the survival analysis.The median OS was 36.10 months (95%CI:18.23 to 42.97 months) and the 1-,3-and 5-year OS rates were 85.3%,46.8% and 27.3%,respectively.The median OS of 41 patients with negative margins was 47.83 months(95%CI:36.90 to 58.80 months) and that of 37 patients with positive margins was 20.47 months(95%CI:10.52 to 30.58 months).The median RFS of 70 patients with R0 and R1 resection was 24.50 months(95%CI:12.15 to 31.85 months)and the 1-,3-and 5-year RFS rates were 65.2%,45.7% and 29.9%,respectively.The median RFS of 41 patients with R0 resection was 38.57 months(95%CI:21.50 to 55.63 months) and that of 29 patients with R1 resection was 10.83 months(95%CI:2.82 to 19.86 months). Conclusions: The primary therapy for pCCA is radical surgical resection.A precise preoperative evaluation and sufficient preparation can reduce postoperative morbidity.Surgical treatment can achieve a better survival outcome by increasing the radical resection rate.

[Rectum-preserving surgery after consolidation neoadjuvant therapy or totally neoadjuvant therapy for low rectal cancer: a preliminary report].

Objective: To investigate the feasibility and safety of sphincter-preserving surgery after neoadjuvant chemoradiotherapy (nCRT) with consolidation chemotherapy in the interval period or total neoadjuvant therapy (TNT) for low rectal cancer. Methods: A descriptive case series study was carried out. Clinical data of patients with locally advanced low rectal cancer (LALRC) who achieved complete clinical response (cCR) or nearly cCR (near-cCR) after nCRT at the Department of Colorectal Surgery of Fujian Medical University Union Hospital from May 2015 to February 2019 were retrospectively analyzed. Case inclusion criteria: (1) Low rectal adenocarcinoma within 6 cm from the anal verge. (2) After nCRT, tumor presented markedly regression as mucosal nodule or abnormalities, superficial ulcer, scar or a mucosal erythema (< 2 cm); no regional lymph node metastasis or distant metastasis was found in rectal ultrasonography, pelvic MRI and PET-CT; MRI showed obvious fibrosis in the original tumor site; and post-treatment CEA was normal. (3) The patient and the family members adhered to receive the transanal full-thickness local excision with informed consent. (4) When the residual lesions were difficult to detect after nCRT, patients received the watch and wait (W&W) strategy. Exclusion criteria: (1) Before nCRT, pathological results showed poorly differentiated or signet-ring cell carcinoma; lateral lymph node metastasis was suspected. (2) When the residual lesion size was more than 3 cm after nCRT, it was difficult to perform local excision. The consolidation nCRT group received 3-4 cycles of CAPOX regimen (oxaliplatin and capecitabine) or six cycles of mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) combined with the long-course radiotherapy (intensity-modulated radiation therapy with a total dose of 50.4Gy). Patients with concurrent chemotherapy more than or equal to five cycles of CAPOX or eight cycles of mFOLFOX6 were defined as total neoadjuvant therapy (TNT) group. Local resection was recommended for patients who were near-cCR according to modified MSKCC criteria 8-33 weeks after the end of radiotherapy. Patients with a near-cCR, who were judged as ycN0 according to PET-CT and MRI and were ypT0 after local excision, could enter the W&W strategy. Patients with pathologic stage more advanced than ypT1, and those with positive resection margin, or lymphovascular invasion were recommended for salvage radical surgery after local excision. The ypT1 patients with a negative resection margin and without lymphovascular invasion might receive the W&W management carefully if they refused radicalsurgery to sacrifice the sphincter for low rectal cancer. Results: Of 32 patients, 14 were males and 18 were females with the average age of 59 years old. Twenty-three patients underwent consolidation nCRT, and 9 received TNT. The first evaluation after treatments showed 19 cases with cCR and 13 with near-cCR. Twenty-nine patients received local excision while 3 patients with undetectable lesions received W&W policy. Four cases (12.5%) underwent salvage radical surgery with abdominoperineal resection. After local excision, 3 cases underwent salvage radical surgery immediately, and the final pathologic result was ypT3N0, ypT2N0, and ypT2N0 respectively, of whom 2 cases were in the group of consolidation CRT and 1 was in the TNT group. Of these 3 cases, 1 case with an initial cT3 stage showed a pathologic stage of ypT1 and a negative circumferential resection margin after consolidation nCRT and local excision, however, the final pathologic stage was ypT3 with fragmented tumor deposits in the mesorectum after the salvage radical surgery. Meanwhile 1 patient in the TNT group receiving W&W suffered from intraluminal regrowth after 7.4 months follow-up and underwent salvage abdominoperineal resection. One patient in the consolidation nCRT group died of stroke 42.5 months after local resection. Another patient in the TNT group had cerebral metastasis 10 months after the W&W policy, but no local recurrence was found in the pelvic cavity, then received resection of the metastatic tumors. The average follow-up for all the patients was 23 (5-51) months. The cumulative local regrowth rate was 5.0%. The overall survival rate was 85.7%, and the sphincter-preservation rate was increased from 25.0% (28/32) in the original plan to 87.5% (28/32) actually. The 3-year disease-free survival rate was 89.7%. The 3-year organ-preserving survival rate was 85.7%, and the 3-year stoma-free survival rate was 82.5%. At present, 31 patients still survived. Conclusions: After nCRT with consolidation chemotherapy or TNT for low rectal cancer, patients with cCR, ycN0 according to PET-CT and MRI, and ypT0 after local excision, can consider the W&W strategy. Strict patient selection with a near-cCR for local resection and sphincter-preserving strategy can reduce the local regrowth of cancer, and the short-term outcomes are satisfactory.

[Identification of gene biomarkers to predict responses to neoadjuvant chemoradiotherapy in patients with rectal cancer and pathways enrichment analysis].

Objective: To screen out the potential gene biomarkers to predict responses to neoadjuvant chemoradiotherapy (CRT) in patients with rectal cancer and to explore the main downstream pathways of resistance. Methods: The gene expression profiles (GSE35452) of locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy from 46 specimens (24 responders, TRG 0/1, and 22 non-responders, TRG 2/3) were downloaded from the GEO database. The differentially expressed genes were identified to screen out the potential biomarkers by use of the GCBI platform. GO and KEGG pathways enrichment analysis were performed to integrate enrichment results of differentially expressed genes. Signal-signal interaction network was constructed and analyzed to screen out potential main downstream pathways. Results: A total of 1079 differentially expressed genes were screened, including 657 up-regulated and 422 down-regulated ones. Among these genes, REG4 had the maximum fold change value of -6.029 491. In GO term, these differentially expressed genes were mainly enriched in molecule metabolic process, cell cycle, DNA-dependent transcription, signal transduction and apoptotic process. The KEGG pathways enrichment analysis showed that the differentially expressed genes were enriched in 65 KEGG pathways, including metabolic pathways, cell cycle and metabolism pathways. Signal-signal interaction network analysis showed that MAPK signaling pathway and cell cycle pathway might play a determinant role in the development of neoadjuvant chemoradiotherapy resistance. Further analysis showed that CDKN1B, CDKN2A, RBL1, TFDP1, CCND2, CCNE2, CDC6 and CDK6 in cell cycle might induce chemoradiotherapy resistance by blocking G1/S phase cell cycle arrest, decreasing the apoptosis of tumor cells and increasing S phase ratio of chemoradiotherapy resistance. Conclusion: G1/S phase cell cycle arrest blocking plays an important role in the development of chemoradiotherapy resistance in patients with rectal cancer. Moreover, the key genes, such as REG4, may be useful in predicting responses to neoadjuvant chemoradiotherapy.

MiRNA-485-5p, inhibits esophageal cancer cells proliferation and invasion by down-regulating O-linked N-acetylglucosamine transferase.

OBJECTIVE: Previous reports suggest that miRNA-485-5p is dysregulated and contributes to tumorigenesis in some cancer types. Nevertheless, the biological role of miRNA-485-5p in esophageal cancer (EC) is not well understood. Additionally, we found that the expression of miR-485-5p in EC tissues was aberrant. PATIENTS AND METHODS: Quantitative RT-PCR (qRT-PCR) was used to demonstrate the expression of miRNA-485-5p in EC cell lines. Cell counting kit-8 (CCK-8) assay and transwell assay indicated that miRNA-485-5p overexpression inhibited cell proliferation, migration, and invasion in EC cell lines. Additionally, Western blotting, dual-luciferase reporter assay, and rescue assay predicted that O-linked N-acetylglucosamine transferase (OGT) was a direct target of miRNA-485-5p. Moreover, we showed that miRNA-485-5p regulated EC tumorigenesis by down-regulating OGT expression in vitro and in vivo. RESULTS: The upregulation of miR-485-5p (fold change = 44 and 26 in ECA109 and TE-1, respectively; p<0.001) was showed by qRT-PCR. Compared with the control groups, the expression miR-485-5p significantly suppressed the proliferation, migration, and invasion of EC cells. The bioinformatic analysis predicted that the 3' untranslated region (UTR) of OGT contains one miR-485-5p target sequences. Western blotting and dual-luciferase reporter assay showed that activation of OGT 3'UTR was increased by co-transfection with miR-485-5p. Finally, CCK-8 assay predicted that the rescue effects of OGT expression on miR-485-5p induced inhibition of cell growth and tumor weight in Eca109 and TE1 cells. CONCLUSIONS: Our results suggest that miRNA-485-5p is a suppressor of EC tumorigenesis and could serve as a novel candidate for therapeutic applications in EC treatment.

Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel.

Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.

[Effects of neoadjuvant chemoradiotherapy on the rates of sphincter preserving surgery in lower rectal cancer and analysis of their prognostic factors].

Objectives: To identify independent factors of sphincter preserving surgery, and to evaluated whether preoperative chemoradiotherapy (CRT) improves the sphincter preservation rate for lower rectal cancers. Methods: A total of 541 consecutive patients who underwent curative surgery for locally advanced rectal cancer (cT3-4Nx or cTxN+ ) within 6 cm of the anal verge with or without neoadjuvant CRT in Department of Colorectal Surgery, Union Hospital, Fujian Medical University between September 2000 and September 2013 were reviewed. Of these, 333 patients underwent surgery alone (Non-CRT group) and 208 patients also received preoperative chemoradiotherapy (CRT group). Clinical data were retrospectively reviewed to determine the factors influencing sphincter preservation, and to evaluate sphincter preservation rate according to tumor height over 1-cm intervals. The categorical variables were compared using χ2 test and Fisher exact test. Continuous variables were compared using t test. Logistic regression was used to identify factors influencing sphincter preservation. A receiver operating characteristic (ROC) curve was constructed, and Youden's index was calculated to evaluate the predictive abilities of factors. Results: Multivariate analysis indicated that the independent factors influencing sphincter preservation were tumor height (OR=5.867, 95% CI: 4.155 to 8.285, P=0.000), pathological T stage (OR=0.688, 95% CI: 0.462 to 1.025, P=0.066), CRT (OR=2.088, 95% CI: 0.971 to 4.492, P=0.060) and histopathological type (OR=0.288, 95% CI: 0.136 to 0.611, P=0.001). The results of ROC analysis showed that the cut-off points for factors affecting sphincter preservation were as follows: (1) tumor height prior to CRT higher than 4.5 cm, (2) not mucinous or signet ring adenocarcinoma, (3) pathological T stage higher than T3, (4) had received preoperative CRT. In an analysis according to tumor height, the sphincter preservation rate was higher in CRT group only when tumor was located in 3.0 to 3.9 cm and 4.0 to 4.9 cm from the annal verge (3.0 to 3.9 cm, 59.4% vs. 2.8%, χ2=26.138, P=0.000; 4.0 to 4.9 cm, 76.9% vs. 37.9%, χ2=10.563, P=0.001). Conclusions: There is a large increased rate of sphincter preservation when patients meet the following conditions: (1) tumor height prior to CRT higher than 4.5 cm, (2) not mucinous or signet ring adenocarcinoma, (3)pathological T stage higher than T3, (4) had received preoperative CRT. Only when tumors are between 3 and 5 cm from the anal verge, CRT could increase the rate of anal sphincter preservation.

[Prognostic factors of postoperative incisional surgical site infections for colorectal cancer].

Objective: To explore the prognostic factors of postoperative incisional surgical site infections (I-SSI) for colorectal cancer. Methods: Clinical data of 2 385 colorectal cancer patients undergoing resection by the same surgical team in Department of Colon and Rectum Surgery, Fujian Medical University Union Hospital from January 2000 to February 2014 was analyzed retrospectively. There were 1 421 male and 964 female patients, with a mean age of (59±13) years. Univariate analysis and multivariate Logistic regression analysis were performed for independent prognostic factors of I-SSI. Results: The I-SSI occurred in 77 patients (3.23%). The results of univariate analysis showed that there were statistical differences in body mass index (t=-3.356), operation time (t=-3.609), length of incision (t=-5.492), radical operation (χ2=8.963), laparoscopic surgery (χ2=25.884), combined evisceration (χ2=6.349) and intraoperative blood infusion (χ2=4.176) between two groups (all P<0.05) . The results of multivariate Logistic regression analysis showed that independent prognostic factors of I-SSI were identified to be body mass index (OR=1.087, 95%CI: 1.023 to 1.155, P=0.007), operation time (OR=1.007, 95%CI: 1.002 to 1.012, P=0.006), preoperative chemoradiotherapy (OR=2.434, 95%CI: 1.099 to 5.393, P=0.028) and combined evisceration (OR=2.596, 95%CI: 1.060 to 6.357, P=0.037). The independent protective prognostic factor of I-SSI was identified to be the laparoscopic surgery (OR=0.386, 95%CI: 0.170 to 0.877, P=0.023). Conclusions: Body mass index, operation time, preoperative chemoradiotherapy and combined evisceration are identified to be independent prognostic factors for I-SSI. High-risk patients should receive individualized perioperative intervention. Nevertheless, the laparoscopic surgery can decrease the incidence of I-SSI.

Team-based model for non-operating room airway management: validation using a simulation-based study.

BACKGROUND: Non-operating room (non-OR) airway management has previously been identified as an area of concern because it carries a significant risk for complications. One reason for this could be attributed to the independent practice of residents in these situations. The aim of the present study was to ascertain whether differences in performance exist between residents working alone vs with a resident partner when encountering simulated non-OR airway management scenarios. METHODS: Thirty-six anaesthesia residents were randomized into two groups. Each group experienced three separate scenarios (two scenarios initially and then a third 6 weeks later). The scenarios consisted of one control scenario and two critical event scenarios [i.e. asystole during laryngoscopy and pulseless electrical activity (PEA) upon post-intubation institution of positive pressure ventilation]. One group experienced the simulated non-OR scenarios alone (Solo group). The other group consisted of resident pairs, participating in the same three scenarios (Team group). RESULTS: Although the time to intubation did not differ between the Solo and Team groups, there were several differences in performance. The Team group received better overall performance ratings for the asystole (8.5 vs 5.5 out of 10; P<0.001) and PEA (8.5 vs 5.8 out of 10; P<0.001) scenarios. The Team group was also able to recognize asystole and PEA conditions faster than the Solo group [10.1 vs 23.5 s (P<0.001) and 13.3 vs 36.0 s (P<0.001), respectively]. CONCLUSIONS: Residents who performed a simulated intubation with a second trained provider had better overall performance than those who practised independently. The residents who practised in a group were also faster to diagnose serious complications, including peri-intubation asystole and PEA. Given these data, it is reasonable that training programmes consider performing all non-OR airway management with a team-based method.

A retrospective analysis of liver resection performed without central venous pressure monitoring.

BACKGROUND: Studies have suggested that blood loss can be reduced during liver resection by monitoring and maintaining low central venous pressure (CVP) through fluid restriction or other means, but such a strategy carries risks to the patient including those inherent to central venous catheterization. We sought to characterize fluid management and blood loss during liver resections done without CVP monitoring. METHODS: Retrospective data were extracted from electronic anesthesia records for 993 liver resections. For 135 resections, between 2011 through 2013, where a documentation template was used that recorded fluid administration prior to hepatic inflow occlusion, multivariate analysis was performed to test for an association between pre-clamp fluid volumes administered and blood loss and other adverse outcomes. RESULTS: The median estimated blood loss was 300 mL and overall rate of transfusion was 8.6%. There was no statistically significant association between crystalloid volume administered prior to inflow clamping (median 900 mL) and blood loss, mortality or length of stay in the subset of patients with supplemental fluid data. CONCLUSION: Liver resection can be performed safely without either CVP monitoring or non-invasive continuous cardiac output monitoring. Additionally, there was no disadvantage to a practical approach to fluid administration prior to inflow clamping during liver resections in the absence of CVP monitoring with regard to blood loss or short-term outcomes.

Selecting stage ypT0-1N0 for locally advanced rectal cancer following preoperative chemoradiotherapy: implications for potential candidates of organ-sparing management.

AIM: Local excision or a wait-and-see policy may offer the possibility of organ preservation for locally advanced rectal cancer (LARC) after preoperative chemoradiotherapy (CRT). Identifying associated factors of good responders (GR) with stage ypT0-1N0 would probably influence the selection of potential candidates who were theoretically eligible for organ-sparing management. This study was to establish a scoring system to select stage ypT0-1N0 for LARC following preoperative CRT. METHOD: Between 2009 and 2014, 262 patients with middle and low LARC were treated with CRT and radical surgery. Clinicopathological data which were found to be significantly associated with GR were incorporated into a scoring system. RESULTS: Fifty-seven (21.8%) patients were GR with stage ypT0-1N0 in the operative specimen. Multivariate analyses indicated that a low level of pretreatment carcinoembryonic antigen (CEA) and post-treatment CEA <2.55 ng/ml (P = 0.008 and P = 0.009 respectively) and long-axis diameter of residual tumours (P = 0.006) were independently associated with stage ypT0-1N0. The three factors were incorporated into a scoring system. Using receiver operating characteristic curve analysis, we determined a cutoff value of -0.3 for scores, at which the system's sensitivity was 71.9% and specificity 73.1%. When applied to testing samples, the sensitivity was 74.1% and specificity 76.2%. CONCLUSION: We demonstrated that low levels of pretreatment and post-treatment CEA and the long-axis diameter of residual tumours were associated with stage ypT0-1N0 for LARC after CRT. Therefore, the three-factor scoring system may be used to select potential candidates for organ-sparing management.

High temperature oxidation of iron-iron oxide core-shell nanowires composed of iron nanoparticles.

This work describes an oxidation process of iron-iron oxide core-shell nanowires at temperatures between 100 °C and 800 °C. The studied nanomaterial was synthesized through a simple chemical reduction of iron trichloride in an external magnetic field under a constant flow of argon. The electron microscopy investigations allowed determining that the as-prepared nanowires were composed of self-assembled iron nanoparticles which were covered by a 3 nm thick oxide shell and separated from each other by a thin interface layer. Both these layers exhibited an amorphous or highly-disordered character which was traced by means of transmission electron microscopy and Mössbauer spectroscopy. The thermal oxidation was carried out under a constant flow of argon which contained the traces of oxygen. The first stage of process was related to slow transformations of amorphous Fe and amorphous iron oxides into crystalline phases and disappearance of interfaces between iron nanoparticles forming the studied nanomaterial (range: 25-300 °C). After that, the crystalline iron core and iron oxide shell became oxidized and signals for different compositions of iron oxide sheath were observed (range: 300-800 °C) using X-ray diffraction, Raman spectroscopy and Mössbauer spectroscopy. According to the thermal gravimetric analysis, the nanowires heated up to 800 °C under argon atmosphere gained 37% of mass with respect to their initial weight. The structure of the studied nanomaterial oxidized at 800 °C was mainly composed of α-Fe2O3 (∼ 93%). Moreover, iron nanowires treated above 600 °C lost their wire-like shape due to their shrinkage and collapse caused by the void coalescence.

Intraoperative arterial blood pressure lability is associated with improved 30 day survival.

BACKGROUND: Arterial blood pressure lability, defined as rapid changes in arterial blood pressure, occurs commonly during anaesthesia. It is believed that hypertensive patients exhibit more lability during surgery and that lability is associated with poorer outcomes. Neither association has been rigorously tested. We hypothesized that hypertensive patients have more blood pressure lability and that increased lability is associated with increased 30 day mortality. METHODS: This was a retrospective single-centre study of surgical patients from July 2008 to December 2012. Intraoperative data were extracted from the electronic anaesthesia record. Lability was calculated as the modulus of the percentage change in mean arterial pressure between consecutive 5 min intervals. The number of episodes of lability >10% was tabulated. Multivariate logistic regression was performed to determine the association between lability and 30 day mortality using derivation and validation cohorts. RESULTS: Inclusion criteria were met by 52 919 subjects. Of the derivation cohort, 53% of subjects were hypertensive and 42% used an antihypertensive medication. The median number of episodes of lability >10% was 9 (interquartile range 5-14) per patient. Hypertensive subjects demonstrated more lability than normotensive patients, 10 (5-15) compared with 8 (5-12), P<0.0001. In subjects taking no antihypertensive medication, lability >10% was associated with decreased 30 day mortality, odds ratio (OR) per episode 0.95 [95% confidence interval (CI) 0.92-0.97], P<0.0001. This result was confirmed in the validation cohort, OR 0.96 (95% CI 0.93-0.99), P=0.01, and in hypertensive patients taking no antihypertensive medication, OR 0.96 (95% CI 0.93-0.99), P=0.002. Use of any antihypertensive medication class reduced this effect. CONCLUSIONS: Intraoperative arterial blood pressure lability occurs more often in hypertensive patients. Contrary to common belief, increased lability was associated with decreased 30 day mortality.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Development of a conceptual model to illustrate the impact of multiple myeloma and its treatment on health-related quality of life.

PURPOSE: Little qualitative research exploring the impact of multiple myeloma (MM) and its treatment on the health-related quality of life (HRQL) of patients has been published. This study aimed to explore the burden of MM symptoms and treatment and the impact of these on HRQL. A model was developed to illustrate key concepts and their interrelationships. METHODS: Patients with MM were recruited to this cross-sectional, qualitative study through a patient panel and at two clinical sites in the USA. An interview discussion guide was developed using a review of published literature and interviews with experienced MM clinicians. In-depth, semistructured telephone interviews with MM patients were conducted to explore their experiences of the disease and its treatment. Data were analyzed using a thematic analysis approach. RESULTS: Twenty MM patients at various stages of treatment participated in open-ended, semistructured interviews. Patients reported both current and previous MM symptoms; most had experienced fatigue and pain. Other commonly reported symptoms were fractures, anemia, neuropathy, aches, and infections. MM treatment was found to have a negative impact on patients' HRQL; treatment-related adverse events included fatigue, neuropathy, insomnia, and gastrointestinal symptoms. MM treatment placed a substantial psychological and physical burden on patients, disrupting social activities, decreasing independence, and impacting on relationships. A model was developed to illustrate the relationship between these concepts. CONCLUSION: The conceptual model developed in this study illustrates the many aspects of MM and its treatment and how they can have a negative impact on patients' HRQL.

Circulating microRNAs are associated with docetaxel chemotherapy outcome in castration-resistant prostate cancer.

BACKGROUND: Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study. METHODS: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. RESULTS: Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together. CONCLUSIONS: Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.

Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality.

BACKGROUND: Anaesthetists have traditionally ventilated patients' lungs with tidal volumes (TVs) between 10 and 15 ml kg(-1) of ideal body weight (IBW), without the use of PEEP. Over the past decade, influenced by the results of the Acute Respiratory Distress Syndrome Network trial, many anaesthetists have begun using lower TVs during surgery. It is unclear whether the benefits of low TV ventilation can be extended into the perioperative period. METHODS: We reviewed the records of 29 343 patients who underwent general anaesthesia with mechanical ventilation between January 1, 2008 and December 31, 2011. We calculated TV kg(-1) IBW, PEEP, peak inspiratory pressure (PIP), and dynamic compliance. Cox regression analysis with propensity score matching was performed to examine the association between TV and 30-day mortality. RESULTS: Median TV was 8.6 [7.7-9.6] ml kg(-1) IBW with minimal PEEP [4.0 (2.2-5.0) cm H2O]. A significant reduction in TV occurred over the study period, from 9 ml kg(-1) IBW in 2008 to 8.3 ml kg(-1) IBW in 2011 (P=0.01). Low TV 6-8 ml kg(-1) IBW was associated with a significant increase in 30-day mortality vs TV 8-10 ml kg(-1) IBW: hazard ratio (HR) 1.6 [95% confidence interval (CI) [1.25-2.08], P=0.0002]. The association remained significant after matching: HR 1.63 [95% CI (1.22-2.18), P<0.001]. There was only a weak correlation between TV kg(-1) IBW and dynamic compliance (r=-0.006, P=0.31) and a weak-to-moderate correlation between TV kg(-1) IBW and PIP (r=0.32 P<0.0001). CONCLUSIONS: Use of low intraoperative TV with minimal PEEP is associated with an increased risk of 30-day mortality.

Influence of increased left ventricular myocardial mass on early and late mortality after cardiac surgery.

BACKGROUND: Increased left ventricular mass (LVM) is a well-recognized predictor of cardiovascular morbidity and mortality in epidemiological studies, but its impact on mortality after cardiac surgery is poorly defined. We hypothesized that patients with increased LVM index (LVMI) were more likely to have greater 30 day and 1 yr mortality. METHODS: With IRB approval, intraoperative transoesophageal echocardiography images of 844 cardiac surgical patients were reviewed. LVMI was calculated using the American Society of Echocardiography recommended formula. Outcome variables studied were 30 day and 1 yr mortality. RESULTS: Mortality within 30 days occurred in 28 patients (3.3%) and within 1 yr in 91 patients (10.8%). An almost linear relationship was found between increasing LVMI and the risk of mortality within 30 days of cardiac surgery. The odds ratio (OR) of dying within 30 days of surgery was 1.15 (95% confidence interval 1.01-1.31) per 20 g m(-2) increase in LVMI. This finding remained statistically significant in multivariate analysis controlling for the effects of age, weight, gender, surgery type, LV function, and functional status [OR=1.36 (1.11-1.66) per 20 g m(-2) increase]. Increased LVMI was not found to be a statistically significant predictor of 1 yr mortality. CONCLUSIONS: Increased LVMI, but not LV systolic function as measured by the fractional area of contraction (FAC) was identified as a strong independent predictor of perioperative mortality after adult cardiac surgery. The relationship between LVMI and risk of 30 day mortality was nearly linear. Furthermore, decreased FAC, and not LVMI, was a strong independent predictor of 1 yr mortality.

Light-sensitive intelligent drug delivery systems of coumarin-modified mesoporous bioactive glass.

Functionalized mesoporous bioactive glasses (MBG) with photoactive coumarin demonstrates photo-responsive dimerization resulting in reversible gate operation. Coumarin-modified MBG was used as a drug delivery carrier to investigate drug storage/release characteristics using phenanthrene as a model drug. Irradiation with UV light (>310 nm) induced photo-dimerization of the coumarin-modified MBG, which led to the pores' closing with cyclobutane dimers and trapping of the guest phenanthrene in the mesopores. However, irradiating the dimerized-coumarin-modified MBG with shorter wavelength UV light (approximately 250 nm) regenerates the coumarin monomer derivative by the photo-cleavage of cyclobutane dimers, such that trapped guest molecules are released from the mesopores. The structural, morphological, textural and optical properties are well characterized by X-ray diffraction, transmission electron microscopy, N(2) adsorption/desorption, and UV-visible spectroscopy. The results reveal that the MBG exhibits the typical ordered characteristics of the hexagonal mesostructure. The system demonstrates great potential in light-sensitive intelligent drug delivery systems and disease therapy fields.